Project 1 - Exploiting Metabolic Vulnerabilities

项目 1 - 利用代谢漏洞

基本信息

批准号：
10242862
负责人：
CHRISTOPHER M SASSETTI
金额：
$ 64.76万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242862
关键词：
Acyl Coenzyme A Amino Acids Animal Model Anti-Bacterial Agents Bacteria Binding Biochemical Biology Carbon Cell Wall Cells Chemicals Complex Critical Pathways Crystallization Development Drug Design Drug Targeting Ensure Enzymes Genetic Genetic Screening Genus Mycobacterium Goals Growth Heme In Vitro Infection Lipids Malate Dehydrogenase Metabolic Metabolic Pathway Metabolism Methods Multienzyme Complexes Mycobacterium tuberculosis Orthologous Gene Pathway interactions Phosphoenolpyruvate Carboxylase Physiological Program Development Prokaryotic Cells Proteins Pyruvate Kinase Resources Role Source Specificity Structure Variant base chemical genetics cofactor design drug development high throughput screening improved inhibitor/antagonist insight interdisciplinary approach multidisciplinary mycobacterial novel pathogen programs protein complex protein function protein structure small molecule small molecule inhibitor structural biology tool

项目摘要

Project Summary – Project 1 - Exploiting metabolic vulnerabilities Central metabolic pathways are critical for bacterial viability and represent a rich source of potential drug targets. However, these enzymes have been under-exploited by anti-bacterial drug development programs for two basic reasons. Firstly, these complex pathways perform diverse roles under different growth states, leaving their importance during infection unclear. In addition, homologous mammalian enzymes often exist, necessitating the design of specific inhibitors. To overcome these complications and exploit this rich source of potential drug targets, we use a combination of genetics and chemical biology to identify druggable metabolic enzymes that are essential in relevant host microenvironments, and employ structural biology to aid in the development of specific inhibitors. These studies have defined target-inhibitor pairs in a broad range of metabolic pathways and regulators. For example, central carbon metabolic enzymes critical for bacterial survival in animal models, such as phophoenolpyruvate carboxykinase (PEPCK), pyruvate kinase (PK), and malate dehydrogenase, have been subjected to structure-guided inhibitor design. Similar approaches have been applied to critical components of lipid anabolic pathways, such as PKS13 and components of acyl-CoA carboxylase complexes, enzymes critical for amino acid and cofactor synthesis, and heme metabolism. These studies have identified potent and specific small molecule inhibitors, revealed novel protein complexes and elucidated the physiological functions of these enzymes in the bacterium.

项目摘要 - 项目1-利用代谢漏洞中央代谢途径对于细菌生存能力至关重要，代表了潜在药物的丰富来源目标。但是，这些酶因抗细菌药物的开发而被解释不足程序的两个基本原因。首先，这些复杂的途径在不同的增长状态，使其在感染期间的重要性不清楚。此外，同源哺乳动物酶通常存在，是存在特定抑制剂的设计所必需的。克服这些并发症并利用这种潜在药物靶标的丰富来源，我们结合了遗传学和化学药品生物学以识别在相关宿主微环境中必不可少的可药物代谢酶，和员工结构生物学，以帮助开发特定的抑制剂。这些研究定义了目标抑制剂对以各种代谢途径和调节剂对。例如，中央碳在动物模型中，对细菌存活至关重要的代谢酶，例如苯酚丙酮酸羧基酶（PEPCK），丙酮酸激酶（PK）和苹果酸脱氢酶已受到约束结构引导的抑制剂设计。类似的方法已应用于脂质的关键成分合成代谢途径，例如PKS13和酰基-COA羧化酶配合物的成分，酶对于氨基酸和辅因子合成至关重要，以及血红素代谢。这些研究已经确定了有效的和特定的小分子抑制剂，揭示了新型蛋白质复合物并阐明了生理这些酶在细菌中的功能。